大肠癌IFN-γ基因+874位点的单核苷酸多态性

目的：探讨中国浙江地区汉族人群中IFN-γ基因 874位点多态性分布,分析其与大肠癌的相关性.方法：应用突变特异性扩增系统(ARMS)- PCR对健康者132例和大肠癌患者92例IFN-γ基因 874位点多态性进行分析,并将PCR产物克隆及测序鉴定.结果：大肠癌患者IFN-γ 874位点AA基因型频率为70.6%,显著高于正常人中的57.6% (P＜0.05).进一步分析显示IFN-γ 874位点AA基因型与患者的年龄、性别、肿瘤部位、Dukes分期无关.结论：IFN-γ 874位点AA基因型可能与大肠癌的发生相关.     

No association between the +874T/A single nucleotide polymorphism in the IFN-gamma gene and susceptibility to TB.

A single nucleotide polymorphism (SNP), +874T/A, in the first intron of the interferon-gamma (IFN-gamma) gene, has presented associations with human susceptibility to tuberculosis (TB) in some ethnic populations, but not in others. In this population-based case-control study with adult TB patients from Houston, Texas, we found no significant differences of + 874T/A genotypic frequencies between cases and ethnically-matched controls or between advanced forms of TB disease (extra-pulmonary involvement or presence of cavitary disease) and pulmonary TB. Given possible sample size limitations, our results suggest that the IFN-gamma +874T/A mutation has no association with TB susceptibility or TB disease severity.     

Association of the interferon-gamma single nucleotide polymorphism +874(T/A) with response to immunosuppressive therapy in patients with severe aplastic anemia

The aim of this study was to investigate whether a single nucleotide polymorphism (SNP) +874T/A of interferon-gamma (IFN-γ) correlates with response to immunosuppressive therapy. Amplification refractory mutation system-polymerase chain reaction was used to amplify the polymorphic segments of the IFN-γ +874T/A gene in the samples obtained from 54 patients with aplastic anemia and 51 healthy adults. Further, enzyme linked immunosorbent assay was used to assay IFN-γ levels in the blood plasma of 35 patients with severe aplastic anemia before immune suppression therapy and 20 healthy blood donors. The results showed that the frequency of IFN-γ +874 TT genotype in patients with aplastic anemia was significantly higher than the corresponding frequency in the healthy adults (42.6% vs. 17.6%, χ(2)=13.78, p=0. 01). The response rate in severe aplastic anemia patients with increased IFN-γ levels in the blood plasma was higher than that in severe aplastic anemia patients with decreased IFN-γ levels in the blood plasma (73.7% vs. 25.0%, p<0.05). Of the 35 patients with severe aplastic anemia, 15 showed the IFN-γ +874 TT genotype, whereas response in 11 patients, the high response rate was significantly in the favor of the IFN-γ +874 TT genotype (73.3% vs. IFN-γ +874 non-TT 35%, p<0.05). In conclusion, the IFN-γ +874T/A gene polymorphism may be correlated with response to immunosuppressive therapy.     

Association between the severity of Hashimoto's disease and the functional +874A/T polymorphism in the interferon-gamma gene

CD8+ CD25+-activated cytotoxic T cells and anti-thyroglobulin antibodies (TgAb) are independently involved in the severity of Hashimoto's disease (HD). Interferon gamma (IFN-gamma) activates cytotoxic T cells. To evaluate the hypothesis that the functional +874A/T polymorphism in the gene encoding IFN-gamma is associated with the severity of HD, we examined the frequencies of this polymorphism in 34 HD patients who developed hypothyroidism (severe HD); 22 untreated, euthyroid HD patients (mild HD); 49 patients with intractable Graves' disease (GD); 16 GD patients in remission; and 57 healthy volunteers. Frequency of the +874T allele, which is associated with high IFN-gamma production, was higher in patients with severe HD than in those with mild HD (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.0-12.4; p = 0.047), but there was no difference in the frequency between GD patients. The difference in the frequency of +874T was observed in the subset of patients with HD negative for TgAb (OR, 8.4; 95% CI, 1.2-57.3; p = 0.029) but not in the subset of patients with HD positive for TgAb. Our data indicate that the +874A/T polymorphism in the IFN-gamma gene is associated with severity of HD.     

干扰素-γ基因+874位点及肿瘤坏死因子-α基因-238位点单核苷酸多态性与HBV宫内感染相关性研究

目的:研究IFN-γ+874位点T/A以及TNF-α-238位点G/A的单核苷酸多态性与HBV宫内感染的相关性。方法:采集HBV标记物单项或多项阳性孕妇的外周血,提取基因组DNA,根据新生儿是否感染HBV将孕妇分为宫内感染组和对照组。利用等位基因特异性PCR检测IFN-γ+874位点等位基因型,利用PCR-RFLP方法检测TNF-α-238位点等位基因型。结果:等位基因特异性PCR可以准确判断IFN-γ+874位点等位基因型,对照组IFN-γ+874位点等位基因频率A为0.562,T为0.438,而宫内感染组A为0.738,T为0.262,两组之间的差异具有统计学意义(χ2=4.38,P=0.036)。TNF-α-238位点等位基因型的检测可以使用PCR-RFLP方法,对照组TNF-α-238位点等位基因频率A为0.146,G为0.854,宫内感染组A为0.262,G为0.738,两组之间的差异无统计学意义(χ2=3.26,P=0.071)。结论:IFN-γ+874位点T/A等位基因与HBV宫内感染具有一定相关性,T等位基因对胎儿HBV宫内感染具有防护作用。TNF-α-238位点G/A等位基因型与HBV宫内感染的关系尚不明确。     

Association of interferon-gamma gene polymorphism (+874A) with arthritis manifestation in SLE

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which genetic factors strongly influence susceptibility. Cytokines such as the interferon-gamma (IFNG) gene play a key role in controlling the immunity and inflammation, and therefore their polymorphisms may affect these genes’ expression levels among individuals. We investigated the frequency of IFNG gene intron (+874) polymorphism, previously reported to be associated with IFNG production, in SLE patients compared to a control group. This population-based case–control study includes 154 SLE patients and 154 healthy control subjects with similar ethnic backgrounds. The genotyping was determined by polymerase chain reaction sequence-specific primer method and using the Chi-squared test for analyzing the association between this single-nucleotide polymorphism and SLE. The allele frequencies of the IFNG (+874) gene polymorphism were not significantly different between SLE patients and control subjects (72.7 vs 77%). However, there was a significant association between A dominance model of inheritance with arthritis (odds ratio = 7.64, 95% confidence interval = 1.56–41.64, P = 0.006, P _c = 0.03). The result suggested that the +874 intron polymorphism of IFNG can be used as the marker for SLE susceptibility with arthritis in the Thai population.     

Analysis of HLA-DQA, HLA-DQB frequencies in a group of Sardinian centenarians

Human leukocyte antigen (HLA) alleles, regulating type and intensity of the immune response, might influence life expectancy. In previous case-control studies the authors have demonstrated that both HLA-DR and -DQ alleles are not associated with longevity in the Sardinian population. On the other hand, association studies are subjected (as part of the homogeneity of the population in terms of geographic origin) to a number of possible confounding factors. Therefore, the authors typed the HLA-DQA1 and HLA-DQB1 alleles in 24 sibs (age range 85 to 97) of 17 centenarians by PCR-SSP. Sib pair analysis showed nonsignificant differences between the observed and expected percentage of DQA* or DQB1* allele sharing. Therefore, these data strengthen the view that class II HLA genes have a marginal effect, if any, on the complex longevity trait.     

Association of a single nucleotide polymorphism of the NPR3 gene promoter with early onset ischemic stroke in an Italian cohort

BackgroundNPR3, located on human chromosome 5 (5p14–p13), encodes the natriuretic peptide receptor type C (NPR-C) that is mainly known as the natriuretic peptide clearance receptor. Involvement of NPR3 in susceptibility to cardiovascular diseases, i.e. hypertension, has been previously shown. With regard to stroke predisposition, evidence for a potential role of genetic variation within or nearby NPR3 has been suggested by a previous genome wide association study.MethodsWe investigated the contribution to early-onset ischemic stroke susceptibility of the NPR3 ? 55 C > A transition by genotyping this variant in an Italian cohort of 368 cases and 335 controls.ResultsIn a multivariable logistic regression analysis adjusting for age, gender, hypertension, hypercholesterolemia, smoking habit and diabetes, a significant association of the ? 55 AA genotype with stroke was observed (OR = 3.2, 95% CI 1.2–8.3, p = 0.016). Remarkably, the polymorphism remained associated with stroke after adjusting for hypertensive status.ConclusionOur observation obtained in an Italian cohort of early onset ischemic strokes suggests that a NPR3 promoter gene variant could have a role on cerebrovascular disease susceptibility.     

Catalytically critical nucleotide in domain 5 of a group II intron.

Domain 5 (D5) is a small hairpin structure within group II introns. A bimolecular assay system depends on binding by D5 to an intron substrate for self-splicing activity. In this study, mutations in D5 identify two among six nearly invariant nucleotides as being critical for 5' splice junction hydrolysis but unimportant for binding. A mutation at another site in D5 blocks binding. Thus, mutations can distinguish two D5 functions: substrate binding and catalysis. The secondary structure of D5 may resemble helix I formed by the U2 and U6 small nuclear RNAs in the eukaryotic spliceosome. Our results support a revision of the previously proposed correspondence between D5 and helix I on the basis of the critical trinucleotide 5'-AGC-3' present in both. We suggest that this trinucleotide plays a similar role in promoting the chemical reactions for both splicing systems.     

Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction

Background Myocardial infarction (MI) is a complex multifactorial and polygenic disorder that is thought to result from an interaction between an individual's genetic makeup and various environmental factors. The purpose of this study was to investigate the association between a novel single nucleotide polymorphism in the prostacyclin synthase gene and MI. Methods and Results By the use of polymerase chain reaction-single-strand conformation polymorphism analysis, we identified a single nucleotide polymorphism, C1117A, in exon 8. This nucleotide change did not cause an amino acid change in codon 373. We performed an association study of the polymorphism in 138 patients and 130 healthy control subjects. Multiple logistic linear regression analysis showed the genotype distributions were significantly different between the control group and the MI group (odds ratio, 2.12; 95% CI, 1.47-3.05, P = .04). The C/C genotype was found more frequently in the MI group than in the control group. Conclusions We conclude that the C1117A polymorphism in exon 8 is associated with risk for MI and may be a genetic marker of MI in Japanese persons. (Am Heart J 2002;143:797-801.)     

Association of a single nucleotide polymorphism in the constitutive androstane receptor gene with bone mineral density

Background:   Nuclear receptors play an important role in bone metabolism. In bone cells, the vitamin D receptor (VDR) and the steroid and xenobiotic receptor (SXR) are activated by vitamin D and vitamin K2, respectively. VDR and SXR are the NR1I subfamily members of nuclear receptors. We speculated that the constitutive androstane receptor ( CAR ), the third member of the NR1I subfamily, also could be implicated in the regulation of bone metabolism. Therefore, we analyzed expression of CAR mRNA in osteoblasts and then examined association of a single nucleotide polymorphism (SNP) in the human CAR gene at intron 2 (IVS2–99C>T, rs2502815) with bone mineral density (BMD).
Methods:   Expression levels of CAR mRNA were analyzed during the culture course of rat primary osteoblasts. Association of an SNP in the CAR gene with BMD was examined in 548 healthy Japanese postmenopausal women.
Results:   CAR mRNA increased at day 16 and then increased during culture of rat primary osteoblasts. The increase of CAR mRNA was parallel with the increase of alkaline phosphatase expression, a differentiation marker of osteoblasts. As a result of association study of an SNP in the CAR gene at intron 2, subjects with the CC genotype ( n  = 208) had significantly higher BMD than subjects with the TT or CT genotype ( n  = 340) (lumbar spine BMD, P  = 0.0185; total body BMD, P  = 0.0416).
Conclusion:   CAR mRNA was expressed and regulated in primary osteoblasts. A genetic variation at the CAR gene locus is associated with BMD, suggesting an involvement of the CAR gene in bone metabolism.     

Angiotensin I converting enzyme (ACE) gene polymorphism in centenarians: different allele frequencies between the North and South of Europe

Variants of the angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE1) gene and the apolipoprotein E gene (APOE) have been suggested to be associated with human longevity. We tested the association between the ACE1 insertion (I allele)/deletion (D allele) polymorphism and longevity in a population from Southern Italy and examined the impact of geographical variation on ACE1 allele frequencies on reported associations from other European countries. ACE1 and APOE genotypes were obtained on 82 centenarians and 252 middle-aged, unrelated subjects or volunteers. No statistically significant differences were found in ACE1 genotype or allele frequencies between centenarians and controls in this Southern Italian population nor was there any observed interaction with APOE alleles that are also reputed to be linked to longevity. However, decreasing gradients in ACE1*I allele frequencies, both in centenarians and controls, with concomitant increases in ACE1*D allele frequencies (particularly the ACE1*D/*D genotype) were observed to be statistically significant from Northern to Southern regions of Europe. These findings did not support the previously reported association between ACE1 polymorphism and longevity. However, there were interesting and significant differences, as one moves from Northern to Southern Europe, with regard to the distribution of ACE1 alleles. Such genetic differences in conjunction with differing environmental factors may explain in part previous results suggesting a role of this polymorphism in longevity.     

Association study between a novel single nucleotide polymorphism of the promoter region of the prostacyclin synthase gene and essential hypertension.

The purpose of this study was to investigate whether an association exists between the promoter region of the prostacyclin synthase gene and essential hypertension (EH). Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we discovered a novel single nucleotide polymorphism (SNP), T-192G, in the 5'-flanking region. We performed an association study using the SNP in 200 patients and 200 controls. The allele frequency distribution in the two groups was not significantly different. Thus, this SNP in the PGIS gene is not associated with EH.